Clinical aspects of the HPA Flashcards
Outline the HP axis
How is the system controlled?
BRAIN: Neurosecretory cells release bioaminergic or peptidergic hormone (median eminance, hypothalamus)
HYPOTHALAMUS: Releases releasing or inhibiting factors
Transported in blood via pituitary portal system
PITUITARY: Secretes trophic hormones (e.g. ACTH) which have an effect on a target organ
NEGATIVE FEEDBACK
Target-organ hormone secretion (e.g. cortisol) has an inhibitory effect on pituitary and hypothalamus
What is the effect of the CRH neuron on the stress response?
Corticotropin releasing hormone (CRH) has both stimulatory and inhibitory effects on the stress response
Which categories of hormone do the adrenal cortices secrete?
What enzyme is involved in the production of cortisol?
- Glucocorticoid (e.g. cortisol)
- Mineralocorticoid (e.g. Aldosterone)
- Sex hormones (e.g. androgens)
11-B-hydroxysteroid dehydrogenase
State 6 effects of glucocorticoids?
- Maintenance of homeostasis in stress (e.g. haemorrhage, anxiety, infection)
- Anti-inflammatory
- Energy balance/metabolism
- Formation of bone and cartilage
- Regulation of BP
- Cognitive function, memory, conditioning
How do patterns of release of glucocorticoids differ between mean data and individual data?
Mean data shows circadian rhythm
Individual data shows pulsatility of hormone release “Ultradian rhythm”- spontaneous pulses of varying amplitude
- Amplitude lower than in circadian trough (in rats)
- Hard to distinguish change in stress response (in humans)
What happens at a glucocorticoid receptor regarding the anti-inflammatory action of glucocorticoids?
Cortisol crosses cell membrane
Forms intracellular GR-HSP complex
Breakdown of complex, GR crosses nuclear membrane and sets off cascade of reactions
How does the affinity of mineralocorticoid receptors change?
Effects of this?
In vitro, the mineralocorticoid receptor has the same affinity for aldosterone as cortisol
Specificity is conferred by a ‘pre-receptor’ mechanism
11-B-HSD2 in kidneys inactivated cortisol, enabling aldosterone to bind to the MR
- '’Gating’’ of glucocorticoid access to nuclear receptors
- amplification of GC signal in target cells
Give 5 symptoms of Cushing’s syndrome (too much cortisol)
- Weight gain
- Central obesity
- Fractures
- Neuropsychiatric disorders (Irritabiliy, depression)
- Bruising
- Oligo/amenorrhea
- Erectile dysfunction
- Muscle weakness
State 5 clinical features of Cushing’s syndrome (too much cortisol)
- (fat deposition over upper back, ‘buffalo hump’, rounded ‘moon’ face)
- Thin arms and legs (central obesity)
- Hirsutism
- Thin skin, easily bruised, pigmented striae
- Diabetes
- Hypertension
- Insulin resistance
- Osteoporosis
State 4 causes of excess cortisol production (Cushing pathogenesis)
- Pituitary adenoma: ACTH-secretory cells (a.k.a Cushing’s disease)
- Adrenal tumor: adenoma (or carcinoma)
- ‘Ectopic ACTH’: carcinoid, paraneoplastic
- Iatrogenic: steroid treatment (‘Cushiingoid’)
State 5 symptoms of Addison’s disease (too little cortisol)
- Patient gradually deteriorates health
- Languid and weak
- Indisposed to either bodily or mental exertion
- Body wastes
- Slight pain is referred to stomach, occasionally vomiting
- Discolouration of skin
State 3 clinical features of Addison’s disease (too little cortisol)
- Hypoglycaemia
- (Postural) hypotension
- Malaise, weakness
- Anorexia/ weight loss
- Increased skin pigmentation: knuckles, palmar creases, mouth, scars
State 4 causes of primary adrenal insufficiency causing insufficient cortisol production
- ‘Addison’s disease’
- Autoimmune disease (common in UK)
- Rarer causes: Metastases, TB
- Decreased production of all adrenocortical hormones
State 2 other causes of hypoadrenalism
- Secondary to pituitary disease (rare)
- Iatrogenic- patients on high dose, long term steroids
Outline the difference between type 1 and type 2 autoimmune polyendocrine syndromes
TYPE 1
- Rare
- Onset in infancy
- Ar (AIRE gene)
- Common phenotype: Addison’s, Hypoparathyroidism, Candidiasis
TYPE 2
- Commoner (still rare)
- Onset: Infancy to adulthood
- Polygenic
- Common phenotype: Addison’s, T1DM, AI Thyroid disease
What is common about autoimmune diseases?
What are the clinical implications of this?
Give 3 examples of autoimmune disease
They may occur together
- High index of suspicion for addition AI endocrine disorders. Consider screening these patients
e.g. T1DM + fatigue, weight loss + hypos –> Addisons?
T1DM + non-specific GI symptoms + diarrhoea –> Coeliac
e.g. T1DM, AITD, gestational/postpartum thyroiditis, coeliac disease, Addison’s, Pernicous anaemia, Alopecia, Vitiligo, Heptatitis, Premature ovarian failure, myaesthenia gravis
How do we assess the HPA?
BASAL
- Blood: cortisol, ACTH
- Urine: Cortisol (requires 24 hour collection)
- Saliva: Cortisol (timing is important, no stress)
- Be aware of circadian/ ultradian rhythm
DYNAMIC
- Stimulated test? (ACTH, CRH, ‘stress’ —> hypoglycaemia)
- Suppressed function? –> Dexamethasone (synthetic glucocorticoid
CLINICAL APPLICATION
Typical results for too much cortisol?
- Area under 24 hour urine collection curve indicative (LARGER)
- Midnight cortisol (blood, saliva) - ‘trough’
- 9am ACTH (with paired cortisol)
- Pituitary/ adrenal/ ectopic ? —> Dexamethasone suppression- sensitive to GC negative feedback @pituitary
What is the dexamethasone test?
- used to assess adrenal gland function by measuring how cortisol levels change in response to an injection of dexamethasone
- It is typically used to diagnose Cushing’s syndrome.
- Dexamethasone is an exogenous steroid that provides negative feedback to the pituitary gland to suppress the secretion of (ACTH).
- It binds to glucocorticoid receptors in the anterior pituitary gland, which lie outside the blood-brain barrier, resulting in regulatory modulation.
- A high dose of dexamethasone exerts negative feedback on pituitary neoplastic ACTH-producing cells (Cushing’s disease), but not on ectopic ACTH-producing cells or adrenal adenoma (Cushing’s syndrome)
CLINICAL APPLICATION
Typical results for too little cortisol?
- 9am cortisol - ‘PEAK’
- SYNACTHen test: adrenal response to ACTH
- trophic effect ACTH on adrenals - Insulin tolerance test
- response to hypoglycaemic stress (can be dangerous!) - U&E (Low Na, High K) in Addison’s
- due to mineralocorticoid deficiency
- can measure RENIN & ALDOSTERONE concentration - Low glucose
CLINICAL APPLICATION
Comment on when you should investigate/ image for endocrine disorders
- Never investigate for endocrine condition unless symptoms and signs indicate. –> Risk of false positive result
- Never image and endocrine gland until you have established the diagnosis biochemically –> Risk of discovering incidentalomas
- Once confirmation of Cushing’s: CXR/MRI pituitary/CT adrenals
- Addison’s patients rarely need imaging unless concern for TB/metastatic cancer
CLINICAL APPLICATION
How is Cushing’s managed?
- Surgical intervention
- transphenoidal adenectomy
- adrenalectomy - Pituitary radiotherapy
CLINICAL APPLICATION
How is Addision’s managed?
- Steroid hormone replacement therapy
- glucocorticoid (usually hydrocortisone over prednesolone)
- dose needs to be increases to cover ‘stressors’ e.g. intercurret illnesses (flu), operations/post-op period
- IV/IM if unable to take pill due to: Nil-mouth, vomiting - Primary adrenal insufficiency need mineralocorticoid replacement therapy (fludrocortisone)
- Secondary adrenal insufficiency dont need fludrocortisone (take other hormone replacement)
CLINICAL APPLICATION
What should be noted about patients on steroids?
- May be on long term, high dose use (e.g. on glucocorticoids) which may suppress endogenous adrenal function
- May be used for anti-inflammatory and anti-immune properties in severe asthma/COPD, temporal artheritis/ polymyalgia rheumatica
- May appear ‘Cushingoid’
- May not mount adequate ‘stress response’
- Steroid treatment SHOULDN’T be stopped suddenly
- Give loading dose for operations
- They should be given ‘steroid treatment card’ to remind doctors
